It is generally accepted that the widely used, partial dopamine D(1) receptor agonist, SKF-38393, does not induce immediate early gene expression in striatal projection neurons unless D(1) receptors are sensitized and uncoupled from D(2) receptors by 6-hydroxydopamine lesions or reserpine treatment. In contrast, this study demonstrates, using quantitative in situ hybridization, that the full D(1) receptor agonist, SKF-82958, induced robust expression of c-fos and zif/268 messenger RNAs in the intact rat striatum, especially in the entire shell and medial and ventral core areas of the nucleus accumbens and olfactory tubercle, and in the cerebral cortex, 45 min after one injection. The induction of the striatal immediate early genes is characterized by (i) induction in only medium-sized spiny neurons, (ii) dose-dependent induction, which correlates well with dose-dependent increases in motor activity, and (iii) blockade by the D(1) receptor antagonist, SCH-23390. The muscarinic cholinergic receptor antagonist, scopolamine, which itself did not alter striatal gene expression, profoundly augmented the behaviors and expression of the two immediate early genes in the ventral and dorsal striatum induced by 0.1, 0.5 and 2.0 mg/kg SKF-82958. However, scopolamine attenuated basal, and SKF-82958-stimulated, expression of c-fos and zif/268 messenger RNAs in the cortex. Scopolamine also enabled SKF-38393 to induce locomotor stimulation and c-fos and zif/268 messenger RNA expression in the normosensitive striatum of the rat when SKF-38393 alone caused no such changes. These data demonstrate an ability of SKF-82958 to induce immediate early gene messenger RNA expression in normosensitive dorsal and ventral striatum. Furthermore, intrinsic muscarinic receptor-mediated cholinergic transmission in the striatum may provide an activity-dependent inhibitory control on striatal D(1) receptor stimulation.